Categorization of Protein Kinases by Combining Data from Cell Biology and Medicinal Chemistry Enables Further Evaluation and Differentiation of the Understudied Kinome

Protein kinases (PKs) are among the most intensely investigated drug targets. Small molecular PK inhibitors (PKIs) are preferred agents for therapeutic intervention. Late in 2025, the 100th PKI reached drug approval by the U.S. Food and Drug Administration. However, current PKI drugs are directed against a limited number of primary PK targets. Thus, numerous PKs comprising the human kinome remain available as potential pharmaceutical targets. In 2019, the U.S. National Institutes of Health reported 162 understudied human kinases including 155 PKs (and seven lipid kinases), referred to as dark kinases or the dark kinome. These kinases were identified primarily considering limited functional information and the lack of detection reagents. Herein, we report a new categorization of the human kinome based on publicly available biological and PKI data. The unified categorization integrates biological and chemical exploration of PKs, introduces new PK categories for target evaluation, and defines the understudied kinome.